Diazepam and propantheline composition

ABSTRACT

Compositions comprising diazepam and propantheline halide, useful in treating gastrointestinal disorders are disclosed.

United States. Patent Lerner et al.

[451 Oct. 24, 1972 DIAZEPAM AND PROPANTHELINE COMPOSITION Inventors: Irwin Lerner, West Caldwell; Robert Paul McGrath, Wayne, both Appl. No.: 85,746

Related US. Application Data Continuation-impart of Ser. No. 793,546, Jan. 23, 1969, abandoned.

US. Cl ..424/244, 424/283 Int. Cl. ..A61k 27/00 Field of Search ..424/244, 283

References Cited OTHER PUBLICATIONS American Drug Index, (1968) pp. 194 & 501. Chem. Abst. (1 63-22815g (1965). Chem. Abst. (2) 66-103922u (1967).

Primary Examiner-Stanley J. Friedman Attorney-Samuel L. Welt, Jon S. Saxe, Bernard S. Leon, Gerald S. Rosen, R. Hain Swope and William M. Farley ABSTRACT Compositions comprising diazepam and propantheline halide, useful in treating gastrointestinal disorders are disclosed.

4 Claims, No Drawings DIAZEPAM AND PROPANTHELINE COMPOSITION RELATED APPLICATIONS This application is a continuation-in-part application of U.S. Pat. application, Ser. No. 793,546, filed Jan. 23, 1969 now abandoned.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions which are therapeutically useful in the treatment of gastrointestinal disorders. Examples of gastrointestinal disorders amenable to treatment by the compositions of this invention include peptic ulcer, hyperchlorhydria, ulcerative or spastic colon, nervous stomach, irritable spastic colon, mucous colitis, duidenitis, gastritis, biliary dyskinesia, pylorospasms, cardiospasm, anxiety states having gastrointestinal manifestations and other functional or organic disorders of the digestive tract.

The present invention relates more specifically to compositions comprising 7-chlorol ,3-dihydrol methyl--phenyl-2I-I- l ,4-benzodiazepin-2-one, hereinafter referred to as diazepam, and B-diisopropylaminoethyl xanthene-9-carboxylate methohalide, hereinafter referred to as propantheline halide.

The combination of diazepam or an acid addition salt thereof with a pharmaceutically acceptable acid and propantheline halide has been found to be extremely effective in the therapeutic treatment of gastrointestinal disorders such as peptic ulcer and the like. This effectiveness is the result of the complete anticholiner gic action of propantheline halide plus the ability of diazepam to effectively relieve the anxiety-tension syndrome often manifest with gastrointestinal disorders of the type described previously.

In addition to the free base of diazepam, any salt thereof with a conventional pharmaceutically acceptable acid, such acid being organic or inorganic in nature, may be utilized in forming the compositions of the present invention. For example, one can use a salt of diazepam with aninorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like or a salt with an organic acid such as acetic acid, benzoic acid, lactic acid, malic acid, benzene or toluene sulfonic acid, maleic acid, salicylic acid and the like. The preferred salt of diazepam for forming the compositions for the present invention is the hydrochloride.

In formulating the compositions of the present invention, the use of propantheline halide indicates a member of the group consisting of propantheline chloride, bromide and iodide with the bromide being preferred.

The compositions of the invention are prepared by mixing together the two active components and, optionally, pharmaceutical adjuvants, and forming the resulting mixtures into suitable oral dosage forms, e.g., pressed or coated tablets. Moreover, the compositions of the present invention can be formulated into solutions, syrups, oily suspensions and the like. Additionally, the compositions of the present invention can be provided in the form of hard shell capsules. If desired, the compositions of the present invention can be formulated into dosage forms suitable for parenteral administration. The methods and techniques by which these various dosage forms are prepared are the conlike; disintegrating'agents such as maize starch; and

lubricating agents such as talc, calcium stearate and the like. Where the compositions of the present invention are to be provided in the form of solutions, syrups, suspensions in oil, etc., examples of conventional adjuvants and excipients employed include water, sugar syrup, vegetable oils such as arachis oil, suitable edible suspending agents, suitable edible sweetening agents and preservatives of the type well known in the pharmaceutical art.

The active ingredients of the invention can also be used in rectal suppository form by mixing them with suppository adjuvant materials, e. g., fatty acid esters of glycerine, or glycols, e.g., cocoa butter, propylene glycol monostearate, by techniques well known to the art.

The ratio of active ingredients which comprise the compositions of the instant invention may vary over a considerable range, for example, from about one to about 25, preferably from about three to about seven and one-half parts by weight of propantheline halide per each part by weight of diazepam or the equivalent amount of a salt thereof with a pharmaceutically acceptable acid. A typical adult dosage of the active ingredients of. the present invention constitutes from about 1 mg. to about 25 mg., preferably from about 2 v mg. to about 10 mg. of diazepam or the equivalent amount of a salt thereof with a pharmaceutically acceptable acid and from about 5 mg. to about 30 mg, preferably from about 7 a mg. to about 15 mg. of propantheline halide. For example, a tablet containing as active ingredients 5 mg. of diazepam and 15 mg. of propantheline bromide would in most therapeutic situations be administered to an adult patient three or four times daily. Smaller dosages are, of course, utilized for children or elderly or debilitated patients. The above ranges are not critical and dosages outside these ranges can be employed since the specific dosages and. relative amounts of active ingredients depend upon the condition being treated and the needs of the patient.

The efficacy of the novel compositions of the present invention has been extensively demonstrated in clinical investigations with patients exhibiting a variety of functional gastrointestinal disorders. One such clinical study has demonstrated the unexpected efiicacy of the compositions of the present invention in the treatment of organic gastrointestinal disorders. This study was conducted on a group of nine patients, both male and female between the ages of 32 and 83, afflicted with organic disorders such as duodenal or pyloric ulcers, some of which were of the bleeding variety and all of which had been confirmed by X-ray. Five of these patients received a daily dosage of from 60 mg. to

mg. of propantheline bromide. The remaining four patients received a daily dosage of from 3 to 8 tablets each containing 5.0 mg. diazepam and 15.0 mg. propantheline bromide.

The investigator who conducted this study rated the ment and the other showed no improvement. These ratings can be transposed to a numerical system as follows: complete remission 4; marked improvement 3; moderate improvement 2; slight improvement 1 no improvement 0. These results are unexpected as diazepam is nowhere in the literature indicated or suggested for the treatment of such organic gastrointestinal diseases.

The unexpectedly superior efiicacy of the novel compositions of the present invention may be further demonstrated by a comparison of antiulcerogenic activity against either active component administered alone. In this experiment exertation ulcers were produced by a modification of the method of A. Robert et al. (Amer. J. Dig. Dis. 497-507, 1970) in which mice were placed in a wire screen drum 8 1% inches in diameter. The drum was then rotated at 12 rpm for three hours. The mice were then removed from the drum, sacrificed and the stomachs examined for incidence of ulcers. Groups of five mice each which had been fasted 48 hours received per os gum acacia solution (control), 10 mgjkg. diazepam suspended in gum acacia solution, 30 mg./kg. propantheline bromide suspended in gum acacia solution and a combination of 10 mg./kg. diazepam and 30 mgjkg. propantheline bromide in a gum acacia vehicle, respectively. The results of these tests are summarized in Table I.

bromide 30 mgJkg. plus diazepam l0 mgJkg.

The resultsof these tests clearly demonstrate the superior efficacy of the compositions of the present invention as well as the improved activity in comparison with that of each of the two active components when administered alone.

The following examples are given to illustrate and not limit the invention.

EXAMPLE 1 The following ingredients were blended together thoroughly to form a premix:

Ingredient mg/tablet Diazepam 5 mg. Propantheline bromide 15 mg. Corn starch 15 mg.

The premix is then combined and blended with the following ingredients:

lngredient mg/tablet Microcrystalline cellulose 60 mg. Lactose 104 mg. Magnesium stearate l mg.

EXAMPLE 2 The process of Example 1 was carried out using the same quantities of ingredients except that 10 mg. of diazepam was utilized in place of 5 mg. and the tablets weighed 205 mg. each.

EXAMPLE 3 The following ingredients were blended thoroughly for about 15 minutes in a suitable container:

Ingredient mg/capsule Diazepam 2 mg. Propantheline 7 A mg. Lactose I49 mg. Corn Starch 30 mg. Magnesium Stearate 1 mg. Tale 5 mg.

The above blend was then passed through a Fitzpatrick Comminuting Machine and then blended for an additional 5 minutes. The mixture was then filled into hardshell capsules, each of which contained about 195 mg.

of the composition.

EXAMPLE 4 The process of Example 3 was carried out using the same quantities except that 7 A mg. of lactose was replaced with 7 Va mg. of propantheline, thus bringing the promantheline content of each 195 mg. capsule to 15 mg.

EXAMPLE 5 Five mg. of diazepam hydrochloride, 15 mg. of propantheline bromide, 38.45 mg. of white beeswax, 96.1 mg. of polyoxyethylene sorbitan mono-oleate (T- ween and 1105.45 mg. of propylene glycol monostearate were mixed together, heated and shaped 6 1. A therapeutic composition for the treatment of propantheline halide is propantheline bromide. gastrointestinal disturbances in humans comprising a 3. A therapeutic composition in accordance with therapeutically inert factor consisting of a pharmacew claim 1 in unit dosage form suitable for internal adtically acceptable carrier and a therapeutically ti ministration wherein said therapeutically active factor factor consisting of three parts by weight propantheline 5 In each O agG umt cOnSlStS essentially of 5 mg. halide and one part by w i ht f di or h diazepam or a sufficient amount of a pharmaceutically equivalent amount of a salt thereof with a pharmaceutiacceptable Salt thereof 9 P i 5 of diazepam cally acceptable a id, and 15 mg. of propanthelme halide. v

2. A therapeutic composition according to claim 1 A composltlOH ficcPrdance 3 Vf/herelfl wherein said salt of diazepam with a pharmaceutically 10 Sald Propamhelme hallde 1S Propamhelme bromlde' acceptable acid is the hydrochloride salt and said 

2. A therapeutic composition according to claim 1 wherein said salt of diazepam with a pharmaceutically acceptable acid is the hydrochloride salt and said propantheline halide is propantheline bromide.
 3. A therapeutic composition in accordance with claim 1 in unit dosage form suitable for internal administration wherein said therapeutically active factor in each dosage unit consists essentially of 5 mg. diazepam or a sufficient amount of a pharmaceutically acceptable salt thereof to provide 5 mg. of diazepam and 15 mg. of propantheline halide.
 4. A composition in accordance with claim 3 wherein said propantheline halide is propantheline bromide. 